Development of human chorionic gonadotropin subunit-beta promoter-based toxic gene therapy for testicular cancer

Abstract

Objectives To develop a new toxic gene therapy using the tissue-specific human chorionic gonadotropin-beta (hCG-β) promoter for testicular cancer. Although most patients presenting with disseminated testicular tumor are cured through the use of chemotherapy with or without surgery, those patients with relapse after initial therapy present a difficult clinical problem. The serum tumor marker hCG-β is frequently elevated in patients with testicular cancer, and the pretreatment and post-treatment levels of serum hCG-β are highly predictive of treatment outcome. Methods Human testicular embryonal carcinoma cell line, NEC 8, a human prostate cancer cell line, PC-3, and a human bladder cancer cell line, WH, were used in this study. A transient expression experiment was used to analyze the activity of a 729-bp hCG-β promoter in all three cell lines. A recombinant adenovirus carrying thymidine kinase (Ad-hCG-β-TK) under control of the hCG-β promoter was generated. The tissue-specific activity of Ad-hCG-β-TK was tested in vitro and in vivo. Results The hCG-β promoter had significantly greater activity in the hCG-β-producing cell line (NEC 8) than in the non-hCG-β-producing cell lines (PC-3 and WH). In vitro, Ad-hCG-β-TK with acyclovir significantly inhibited NEC 8 growth but not PC-3 or WH cell growth. In vivo, Ad-hCG-β-TK with acyclovir significantly inhibited NEC 8 subcutaneous tumor growth in nude mice. Conclusions In this study, we explored the possibility of developing a new therapeutic agent to target and induce the killing of testicular germ cell tumor selectively by using tissue-specific hCG-β promoters.